Recent studies from our laboratory and others have emphasized the role of inflammation, and in particular adaptive immunity in hypertension. We have previously shown that various hypertensive stimuli, including angiotensin II, high salt and catecholamines cause T cell activation and entry of T cells with an effector phenotype into the vasculature and the kidney. Mice lacking T cells are protected against hypertension and much of the end-organ damage caused by these stimuli. Recently, we have found that CD8+ T cells are the subtype responsible for this effect, and our preliminary data show that chronic angiotensin II infusion stimulates CD8+ cells to produce the inflammatory cytokines IL-17 and IFN-g. We also have found that mice lacking these cytokines are partially protected against development of hypertension. In the present studies, we will further elucidate the mechanisms by which CD8+ cells are activated and cause hypertension.
In aim one we will employ adoptive transfer techniques to examine the effect of replenishing normal CD8+ cells or CD8+ cells lacking either IL-17 or IFN-g in RAG-1-/- mice. Studies will be performed to determine how these CD8+ cell- derived cytokines affect renal and vascular function and lead to end-organ damage. In preliminary studies for aim 2, we have found that angiotensin II infusion causes dendritic cell activation and that these activated dendritic cells stimulate T cells to proliferateand produce IL-17 and IFN-g.
In aim 2, we will gain further understanding of this by examining the subtype of dendritic cell involved and the sites of dendritic cell activation that are most importat for stimulation of CD8+ T cells. In preliminary studies for aim 3, we have found that angiotensin II infusion increases dendritic cell superoxide production by the NADPH oxidase. We propose experiments to understand how this contributes to hypertension and T cell activation by using mice with dendritic cell-specific deletion of the critical NADPH oxidase subunit p22phox. A potentially important effect of the formation of superoxide and other reactive oxygen species is formation of isoprostanes, which can rearrange to form highly reactive gamma ketoaldehydes or isoketals. These, in turn, can form covalent adducts with protein lysines and have myriad effects on cell function. We have preliminary data showing that isoketals are increased in tissues and dendritic cells by angiotensin II and that isoketal scavenging prevents hypertension.
In aim 4, we will test the hypothesis that isoketal formation in dendritic cells plays a major downstream role in dendritic cell immunogenicity, activation of CD8+ cells and ultimately in hypertension. These studies will provide new insight into the immune mechanisms of hypertension and its concomitant end-organ damage. Moreover, our studies with isoketal scavengers promise to provide a new therapeutic option for treatment of this devastating disease.
High blood pressure is an enormous health care burden in the United States, affecting one in three adults. It is a major cause of stroke, heart attack and kidne disease;however, the causes of hypertension remain poorly understood and treatment is not always successful. In our proposed studies, we will further define the inflammation that causes hypertension and develop new strategies to prevent this.
| Loperena, Roxana; Van Beusecum, Justin P; Itani, Hana A et al. (2018) Hypertension and increased endothelial mechanical stretch promote monocyte differentiation and activation: roles of STAT3, interleukin 6 and hydrogen peroxide. Cardiovasc Res 114:1547-1563 |
| Norlander, Allison E; Madhur, Meena S; Harrison, David G (2018) The immunology of hypertension. J Exp Med 215:21-33 |
| Tran, Anh Nhat; Walker, Kiera; Harrison, David G et al. (2018) Reactive species balance via GTP cyclohydrolase I regulates glioblastoma growth and tumor initiating cell maintenance. Neuro Oncol 20:1055-1067 |
| Pandey, Arvind K; Singhi, Eric K; Arroyo, Juan Pablo et al. (2018) Mechanisms of VEGF (Vascular Endothelial Growth Factor) Inhibitor-Associated Hypertension and Vascular Disease. Hypertension 71:e1-e8 |
| Dikalova, Anna E; Itani, Hana A; Nazarewicz, Rafal R et al. (2017) Sirt3 Impairment and SOD2 Hyperacetylation in Vascular Oxidative Stress and Hypertension. Circ Res 121:564-574 |
| Foss, Jason D; Kirabo, Annet; Harrison, David G (2017) Do high-salt microenvironments drive hypertensive inflammation? Am J Physiol Regul Integr Comp Physiol 312:R1-R4 |
| Guzik, Tomasz J; Skiba, Dominik S; Touyz, Rhian M et al. (2017) The role of infiltrating immune cells in dysfunctional adipose tissue. Cardiovasc Res 113:1009-1023 |
| Grome, Heather N; Barnett, Louise; Hagar, Cindy C et al. (2017) Association of T Cell and Macrophage Activation with Arterial Vascular Health in HIV. AIDS Res Hum Retroviruses 33:181-186 |
| Loperena, Roxana; Harrison, David G (2017) Oxidative Stress and Hypertensive Diseases. Med Clin North Am 101:169-193 |
| Oh, Young S; Berkowitz, Dan E; Cohen, Richard A et al. (2017) A Special Report on the NHLBI Initiative to Study Cellular and Molecular Mechanisms of Arterial Stiffness and Its Association With Hypertension. Circ Res 121:1216-1218 |
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